Accessing the human trophoblast stem cell state from pluripotent and somatic cells

Abstract

Trophoblasts are specialized epithelial cells that perform critical functions during blastocyst implantation and mediate maternal–fetal communication during pregnancy. However, our understanding of human trophoblast biology remains limited since access to first-trimester placental tissue is scarce, especially between the first and fourth weeks of development. Moreover, animal models inadequately recapitulate unique aspects of human placental physiology. In the mouse system, the isolation of self-renewing trophoblast stem cells has provided a valuable in vitro model system of placental development, but the derivation of analogous human trophoblast stem cells (hTSCs) has remained elusive until recently. Building on a landmark study reporting the isolation of bona fide hTSCs from blastocysts and first-trimester placental tissues in 2018, several groups have developed methods to derive hTSCs from pluripotent and somatic cell sources. Here we review the biological and molecular properties that define authentic hTSCs, the trophoblast potential of distinct pluripotent states, and methods for inducing hTSCs in somatic cells by direct reprogramming. The generation of hTSCs from pluripotent and somatic cells presents exciting opportunities to elucidate the molecular mechanisms of human placental development and the etiology of pregnancy-related diseases.

Controlling placental spheroid growth and phenotype using engineered synthetic hydrogel matrices

“…67 JEG-3, JAR, and BeWo cells lines originate from human choriocarcinoma and while they are often used to model invasion, migration, and syncytialization of the human placenta, these cells are unlikely to recapitulate the behavior of healthy tissue. The synthetic hydrogel 3D culture model described in this work can be applied to more physiologically relevant cells to study placental development and microenvironment, such as induced pluripotent stem cell-derived trophoblasts 29,68 and primary trophoblast stem cells. [69][70][71] Cell processes such as invasion, migration, and signaling rely heavily on dynamic protein expression, interactions with ECM, and integrin expression, and our data with JEG-3, JAR, and BeWo demonstrate that a 3D synthetic hydrogel can provide these necessary cues.…”

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

“…To overcome this problem, a study merged syncytiotrophoblasts’ cell layers on semi-permeable supports. These cell layers of syncytiotrophoblasts can act as a sufficient barrier concerning both low- and high-molecular-weight xenobiotic compounds [ 30 , 31 ].…”

Analysis of regulatory network modules in hundreds of human stem cell lines reveals complex epigenetic and genetic factors contribute to pluripotency state differences between subpopulations

“…TEAD signaling is strongly implicated in the differentiation of hiPSC to the trophoblast lineage 41 ; and recently Dattani et al 42 showed that suppression of YAP/TEAD signaling was critical to the insulation of naive hiPSC from trophoblast differentiation. Though the capacity for conventional hiPSC to undergo trophoblast differentiation has been the subject of considerable controversy 41,43 , it is certainly possible that formative state cells, closer to the naïve-state, might be capable of entering this differentiation pathway, and that regulatory elements in RMN 3 are in some way primed for activation in naïve and formative state cells 44 . RNM 8 was strongly enriched for G 1 cell cycle-associated TFs (E2F Family, E2F2, E2F5, SP-E2F Complex) which is consistent with the fact that the formative state has a highly proliferative phenotype and an abbreviated G 1 phase 1,45 (Figure 3A-C).…”

“…To further demonstrate the utility of annotating the ATAC-seq peaks in the RNMs (pluripotency state, chromatin state, and predicted TFBSs), we plotted a 2 MB interval on chromosome 4 surrounding SMAD1 , which is a transcription factor involved in early cell fate decisions during specification of trophoblast and amnion, and later, gastrulation 41,49,50 via regulation of bone morphogenic proteins (BMPs). We observed nine formative-state associated peaks and multiple peaks binding SMAD Family (SMAD2 and SMAD4) and SOX-LEF1 Complex (SOX2, SOX3, SOX4, LEF1) TFs (Figure 3D).…”

“…We demonstrate that trophoblast-specific peaks are enriched with RNM 3 peaks and TEAD Family binding sites (Figure 4C-D), which is consistent with previous observations that TEAD4 is a pioneering factor for the placental lineage commitment 63 . Recently much effort has been put into developing efficient trophoblast differentiation protocols to study common pregnancy-related diseases, such as preeclampsia 41,43,44,53 . RNM 3 may serve as a resource to identify regulatory elements that are early determinants of trophoblast cell fate commitment.…”